Guidelines for identification of, advocacy for, and intervention in neurocognitive problems in survivors of childhood cancer: a report from the Children's Oncology Group

With modern therapies and supportive care, survival of childhood cancer has increased considerably. Patients who have survived cancers involving the central nervous system or who have received therapy toxic to the developing brain are at risk of long-term neurocognitive sequelae. Negative outcomes are observed most frequently in survivors of acute lymphoblastic leukemia and brain tumors. The Children's Oncology Group Long-term Follow-up Guidelines Task Force on Neurocognitive/Behavioral Complications After Childhood Cancer has generated risk-based, exposure-related guidelines designed to direct the follow-up care of survivors of pediatric malignancies based on a comprehensive literature review and expert opinion. This article expands on these guidelines by reviewing the risk factors for the development of neurocognitive sequelae and describing the expected pattern of these disabilities. We herein present recommendations for the screening and management of neurocognitive late effects and outline important areas of school and legal advocacy for survivors with disabilities. Finally, we list resources that can guide patients, their parents, and their medical caregivers as they face the long-term neurocognitive consequences of cancer therapy.     

Monitoring for cardiovascular disease in survivors of childhood cancer: report from the Cardiovascular Disease Task Force of the Children's Oncology Group

Curative therapy for childhood cancer has improved significantly in the last 2 decades such that, at present, approximately 80% of all children with cancer are likely to survive > or = 5 years after diagnosis. Prevention, early diagnosis, and treatment of long-term sequelae of therapy have become increasingly more significant as survival rates continue to improve. Cardiovascular disease is a well-recognized cause of increased late morbidity and mortality among survivors of childhood cancer. The Children's Oncology Group Late Effects Committee and Nursing Discipline and Patient Advocacy Committee have recently developed guidelines for follow-up of long-term survivors of pediatric cancer. A multidisciplinary task force critically reviewed the existing literature to evaluate the evidence for the cardiovascular screening recommended by the Children's Oncology Group guidelines. In this review we outline the clinical manifestations of late cardiovascular toxicities, suggest modalities and frequency of monitoring, and address some of the controversial and unresolved issues regarding cardiovascular disease in childhood cancer survivors.     

Long-term follow-up of pediatric cancer survivors: education, surveillance, and screening

Cancer and its treatment predispose childhood cancer survivors to chronic or late occurring health problems that may not become clinically significant until many years after therapy. Frequently, long-term survivors of childhood cancer report late cancer-related effects that diminish quality of life and increase the risk of early mortality. Risk-based health care that involves a personalized plan for surveillance, screening, and prevention is recommended to reduce cancer-related morbidity in childhood cancer survivors. To implement optimal risk-based care, the survivor and health care provider must have accurate information about cancer diagnosis, treatment modalities, and potential cancer-related health risks to guide screening and risk-reducing interventions. However, previous studies evaluating health knowledge of childhood cancer survivors demonstrate noteworthy deficits and misperceptions about their cancer diagnosis, treatment, and cancer-related health risks. In addition, because of the relative rarity of childhood cancer, many health care providers lack familiarity with cancer-related health risks and risk-reduction methods relevant for this population. To correct these deficits, the Scottish Intercollegiate Guidelines Network (SIGN) and the Children's Oncology Group (COG) developed clinical practice guidelines to foster appropriate risk-based survivor care. Herein, we discuss the development, benefits, and limitations of the SIGN and COG guidelines and the foundation they provide for standardizing long-term follow-up care of the ever-growing vulnerable population of childhood cancer survivors.     

Survivors of childhood cancer: long-term edocrine and metabolic problems dwarf the growth distrubance

The long-term effects of radiotherapy and chemotherapy are becoming increasingly reconginzed as the cure rates of certain childhood malignancies improve. The endocrine system is particularly sensitive to cancer therapies. Long-term survivors of childhood cancer who received cranial irradiation have been shown to have lower than predicted height, an increased prevalence of obesity and redutions in strength, exercise tolerance, bone mineral density, quality of life and academic achievement. Growth hormone deficiency (GHD) is the most frequent endocrine deficiency observed following cranial irradiation. Adults with GHD resulting from primary hypothalamic-pituitary disease during childhood have been shown to exhibit a clinical picture similar to that described in long-term survivors of childhood cancer: increased fat mass and reduced lean mass, strength, exercise tolerance, bone mineral density and quality of life. This review considers the possible contributin of GHD to the adverse sequelae observed in long-term survivors of childhood malignancy and includes our preliminary experience in treating 14 adults with GHD resulting from the treatment of childhood malignancies.     

Renal late effects in patients treated for cancer in childhood: a report from the Children's Oncology Group

Improvements in childhood cancer therapy have led to increasing numbers of long-term survivors. These survivors are at risk for a variety of late effects due to the disease itself, treatment exposures (surgery, chemotherapy, and radiotherapy), underlying medical problems, and health behaviors. The COG LTFU Guidelines are risk-based, exposure-related recommendations for the identification and management of late effects due to therapies utilized in the treatment of childhood cancer, and are designed for asymptomatic survivors presenting for routine medical follow-up 2 or more years after completion of cancer therapy. The COG Guidelines Task Force on Urinary Tract Complications conducted an extensive review of the medical literature via MEDLINE. Specific treatment exposures which were reviewed include nephrectomy, chemotherapy regimens known to be nephrotoxic (cisplatin, carboplatin, ifosfamide, and methotrexate), and renal irradiation. Literature sources were ranked according to the strength of evidence and are cited in the review. This review summarizes the literature that supported the recommendations for cancer survivors at risk for nephrotoxicity previously outlined in the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent and Young Adult Cancers (COG LTFU Guidelines).     

Long-term endocrine sequelae of childhood cancer

PURPOSE OF REVIEW: To update knowledge related to the long-term endocrine sequelae of childhood cancer. RECENT FINDINGS: Endocrine deficiencies are common after cranial irradiation, chemotherapy and specific tumors. These deficiencies include growth hormone, thyrotropin, adrenocorticotropin and gonadotropin deficiencies, primary hypothyroidism, gonadal failure and obesity. Recent studies highlight the impact of radiation on the development of endocrine sequelae. Risks for obesity after childhood tumors include hypothalamic injury, with inactivity and daytime sleepiness. About 6% of adult female survivors of childhood cancer develop persistent ovarian failure. Risks for ovarian damage include ovarian irradiation and alkylating agents. Appropriate fertility-preservation options should be offered. Offspring of women who had uterine irradiation as children are more likely to be born preterm or have low birth weight. Secondary neoplasia or relapse should be considered when treating endocrine deficiencies in cancer survivors. Risk of secondary neoplasia is increased following radiation exposure and certain malignancies. Treatment with growth hormone does not increase cancer recurrence, but survivors may have a 2-fold risk of developing a secondary solid tumor, most commonly a meningioma. SUMMARY: Standardized, multidisciplinary long-term surveillance is important in childhood cancer survivors to identify and treat endocrine and other late effects of cancer and its therapy.     

Late effects on the urinary bladder in patients treated for cancer in childhood: a report from the Children's Oncology Group

Childhood cancer survivors who have had pelvic or central nervous system surgery or have received alkylator-containing chemotherapy or pelvic radiotherapy as part of their cancer therapy may experience urinary bladder late effects. This article reviews the medical literature on long-term bladder complications in survivors of childhood cancer and outlines the Children's Oncology Group Long-Term Follow-up (COG LTFU) Guidelines related to bladder function. An overview of the treatment of bladder late effects and recommended counseling for survivors with these complications are presented.     

Survivors of childhood cancer: long-term endocrine and metabolic problems dwarf the growth disturbance

The long-term effects of radiotherapy and chemotherapy are becoming increasingly recognized as the cure rates of certain childhood malignancies improve. The endocrine system is particularly sensitive to cancer therapies. Long-term survivors of childhood cancer who received cranial irradiation have been shown to have lower than predicted height, an increased prevalence of obesity and reductions in strength, exercise tolerance, bone mineral density, quality of life and academic achievement. Growth hormone deficiency (GHD) is the most frequent endocrine deficiency observed following cranial irradiation. Adults with GHD resulting from primary hypothalamic-pituitary disease during childhood have been shown to exhibit a clinical picture similar to that described in long-term survivors of childhood cancer: increased fat mass and reduced lean mass, strength, exercise tolerance, bone mineral density and quality of life. This review considers the possible contribution of GHD to the adverse sequelae observed in long-term survivors of childhood malignancy and includes our preliminary experience in treating 14 adults with GHD resulting from the treatment of childhood malignancies.     

Nachsorge von Patienten mit Krebs im Kindes- und Jugendalter

Over the last 50 years, improvements in treatments for childhood cancer have led to the extremely gratifying result of survival rates that now exceed 75%. However, about two-thirds of the patients will suffer from late effects of chemotherapy and/or radiotherapy. Anthracycline-induced cardiotoxicity, hearing impairment caused by platinum compounds, and endocrine disturbances related to radiation therapy are three commonly observed sequelae that afflict childhood cancer survivors. Systematic prospective aftercare of these patients is particularly important and is necessary in order to detect and treat organ impairment as soon as possible. The Late Effects Surveillance System (LESS) is a national aftercare network established by the German Association of Paediatric Oncology and Haematology (GPOH). In collaboration with therapy optimisation studies and other working groups of the GPOH, LESS gives recommendations for follow-up and fulfils advisory functions. A future aim is to develop treatments that will avoid major late effects.     

Late effects risk profiles using the long-term follow-up guidelines in identical twin survivors of acute lymphoblastic leukemia

As the number of pediatric cancer survivors increases, the cost of cure (i.e., late effects) needs to be measured through a consistent mechanism. Through the use of the Children's Oncology Group's (COG) Long-Term Follow-Up (LTFU) guidelines, individualized risk profiles can be discerned for each off-therapy patient. These guidelines were used to compare and contrast risk profiles for identical twin females treated for acute lymphoblastic leukemia (ALL). The first twin was treated for high-risk leukemia and the second for standard-risk leukemia, each with different ALL protocols. Timely use of the LTFU guidelines has aided in identifying and treating their adverse late effects.     

Long-term follow-up of childhood cancer survivors: future directions for clinical care and research

Improvement in survival after childhood cancer has resulted in a growing population of childhood cancer survivors, causing the healthcare community to focus on providing appropriate care to the survivors, and addressing issues related to the etiology and prevention of long-term sequelae of cancer and its treatment. The overarching goal is to decrease the morbidity related to cancer treatment, and improve the overall quality of life, such that cancer survivors can successfully integrate back into society and lead productive lives. In order to achieve this goal, several issues need to be addressed, such as education of survivors and healthcare providers regarding the potential late effects; provision of standardized guidelines for appropriate follow-up of the survivors in a setting that is feasible and practical for the cancer survivor; ongoing communication between the cancer center that provided acute care for the patient and the healthcare facility providing follow-up care. Several challenges remain in addressing these issues, and will be the focus of this article.     

Hepato‐biliary late effects in survivors of childhood and adolescent cancer: A report from the Children's Oncology Group

Curative therapy for childhood and adolescent cancer translates to 1 in 640 young adults being a survivor of cancer. Although acute hepato‐biliary toxicity occurs commonly during pediatric cancer therapy, the impact of antineoplastic therapy on long‐term liver health in childhood/adolescent cancer survivors is unknown. This article reviews the medical literature on late liver dysfunction following treatment for childhood/adolescent cancer. We also outline the Children's Oncology Group (COG) guidelines for screening and follow‐up of hepato‐biliary sequelae. As the population of survivors grow and age, vigilance for risks to hepatic health needs to continue based on specific exposures during curative cancer therapy. Pediatr Blood Cancer 2010;54:663–669. © 2009 Wiley‐Liss, Inc.     

Endocrine complications of neoplastic diseases in children and adolescents.

Because of the increasing population of childhood cancer survivors, there is a need to focus on the late effects of cancer therapy. After discharge by their pediatric oncologists, it is essential that patients are not lost to the health system but rather are under continued surveillance with access to the appropriate physicians. Endocrine and metabolic consequences may impact the life of the patient both soon after cancer treatment and for many years in the future. The purpose of this article is to explore the current literature in the following areas: growth hormone (GH) deficiency, gonadotropin-releasing hormone (GnRH) analogues with GH therapy in childhood, safety of GH replacement, cardiovascular risk factors, osteopenia, thyroid problems, and gonadal damage resulting in infertility.     

Cross-sectional study of bone mineral density in adult survivors of solid pediatric cancers

To investigate the hypothesis that survivors of pediatric solid cancer have low bone mineral density, a cross-sectional study was done of subjects who had received treatment for pediatric solid tumors before 16 years of age and were less than 40 years old at follow-up. Excluded were subjects treated for acute lymphoblastic leukemia or those who had received cranial irradiation, total body radiation, or nonautologous bone marrow transplant. The study group consisted of 38 subjects, with the most common diagnoses being lymphoma (n = 17), sarcoma (n = 8), Wilms tumor (n = 5), and neuroblastoma (n = 4). Median age was 22 years (range 12-32). Time from diagnosis of underlying cancer averaged 12.6 years (range 5.5-20.3). Using criteria of osteopenia (Z-score < or = -1.0 and > -2.0) and osteoporosis (Z-score < or = -2.0) for any one or more areas including total body, lumbar spine, total hip, or femoral neck density, 13 of the 38 subjects (34%) had osteopenia or osteoporosis. A further six subjects (16%) had isolated upper extremity osteopenia or osteoporosis. Multivariate analysis showed a direct relationship between the number of chemotherapy drugs administered and the presence of osteopenia or osteoporosis in the lower extremities (P = 0.03). Young survivors of childhood solid tumors are at increased risk of developing premature osteopenia or osteoporosis, and screening evaluations and follow-up are warranted.     

Prospective evaluation of late effects after childhood cancer therapy with a follow-up over 9 years

Intensive multimodality treatment has led to a remarkable improvement of prognosis in paediatric cancer patients, however, a great number of long-term survivors suffer from considerable tumour- or treatment-related late effects. Between January 1990 and December 1998, 223 consecutive survivors of childhood malignancies entered a prospective follow-up study designed to evaluate the frequency and severity of tumour- and/or therapy-related long-term sequelae. After cessation of therapy and subsequently once a year, all patients underwent a detailed examination programme including physical examination, laboratory tests, abdominal sonography, echocardiography, electrocardiography, electroencephalography, spirometry, audiometry, ophthalmological examination and endocrine stimulation tests. Median follow-up was 5 years (range 0.4 to 9.6 years). A total of 167 patients (75%) had at least one chronic medical problem of whom 80 needed permanent medical support. The organ systems most frequently affected were the nervous system in 39%, the endocrine system in 32%, the ears/eyes in 22%, the kidneys in 17%, and the liver in 12% of the patients. Some late effects (endocrine deficits, hearing loss, tubulopathy) were primarily diagnosed only several years after the end of oncological therapy. Conclusion The results of this study indicate that a considerable number of former paediatric cancer patients suffer from remarkable long-term side-effects. Since life quality is an important parameter of cancer survival, careful follow-up of long-term survivors is mandatory with the aim to reduce or even abrogate possible side-effects at the earliest time. Received: 8 December 1999 and in revised form: 1 March 2000 / Accepted: 31 March 2000     

Models of care for survivors of childhood cancer

With improvements in therapy for childhood cancer, the expectation that most childhood cancer patients will survive and enter adulthood is a reality. There is clear evidence that survivors are at risk for adverse health-related long-term sequelae associated with their cancer and its treatment, requiring appropriate health care resources. What is less clear is how this health care should optimally be delivered. We review the functional and operational needs for long-term follow-up for childhood cancer survivors and present alternatives for models of care. Programs for childhood cancer survivors should provide mechanisms for monitoring and management of late effects, as well as support and advocacy for addressing psychosocial issues, health education, and assistance with financial concerns. Access to research is an important component as clinical care and research are integrally related. A multidisciplinary model that provides continuity of care throughout the disease course is optimal, providing transitions from acute anti-neoplastic therapy to follow-up and primary care, as well as from pediatric care to adult-oriented care. There is no single best model of care for all childhood cancer survivors. In evaluating different models, considerations include available resources as well as the particular cancer population being served. Not all survivors require the same level of services and the service level requirement for individual patients may change with time. As outcome research progresses for childhood cancer survivors, methodological issues of optimal health care delivery for this population deserve to be the subject of such research.     

Obesity in pediatric oncology

Today's obesity pandemic began in the United States, spread to Western Europe and other developed regions, and is emerging in developing countries. Its influences on outcomes of childhood cancer are unknown. A recent Children's Oncology Group symposium considered epidemiology of obesity, pharmacology of chemotherapy and outcomes in obese adults with cancer, excess mortality in obese pediatric patients with acute myeloid leukemia (AML), and complications in obese survivors. The salient points are summarized herein. Body mass index (BMI) is the accepted index of weight for height and age. In the US, obesity prevalence (BMI > 95th centile) is increasing in all pediatric age groups and accelerating fastest among black and Hispanic adolescents. Pharmacologic investigations are few and limited: half-life, volume of distribution, and clearance in obese patients vary between drugs. Obese adults with solid tumors generally experience less toxicity, suggesting underdosing. For patients undergoing bone marrow transplantation, obese adults generally experience greater toxicity. In pediatric acute myeloblastic leukemia, obese patients have greater treatment-related mortality (TRM), similar toxicity and relapse rates, and inferior survival compared with patients who are not obese. An excess of female survivors of childhood leukemia who received cranial irradiation are obese. Ongoing treatment effects of childhood cancer may predispose to a sedentary lifestyle. These findings call for measures to prevent obesity, retrospective and prospective studies of chemotherapy pharmacology of analyzed according to BMI and outcomes, additional studies of the obesity impact on outcomes in pediatric cancer, and promotion of a healthy lifestyle among survivors.     

Late effects of treatment for germ cell tumors during childhood and adolescence

PURPOSE: To evaluate the long-term sequelae of treatment for malignant germ cell tumors (GCT) during childhood and adolescence. PATIENTS AND METHODS: Of 128 patients treated for GCT at St. Jude Children's Research Hospital between 1962 and 1988, 73 are long-term survivors (continuously disease-free for > or =5 years after diagnosis), with a median follow-up of 11.3 years). Survivors' ages at diagnosis ranged from birth to 18.3 years (median, 9.2 years); 64% (47 patients) were female. Initial surgical resection was followed by observation for stage I germinomas (n = 2), testicular tumors (n = 13), and selected cases of ovarian or sacrococcygeal tumors (n = 2), and by radiation therapy (RT) for patients with stage II to III germinoma (n = 8). The remaining 48 patients received postoperative chemotherapy (vincristine, dactinomycin, and cyclophosphamide [VAC] +/- doxorubicin, 1962 to 1978; VAC and/or cisplatin, vinblastine, and bleomycin [PVB], 1979 to 1988). RT was added to the chemotherapy for 21 patients. Late complications involving various organ systems and their relationship to treatment were evaluated. RESULTS: More than two-thirds of long-term survivors (n = 50) had at least 1 complication, and half (n = 38) had > 1 organ system affected. The systems most often involved included the musculoskeletal (41% of survivors), endocrine (42%), cardiovascular (16% excluding those who had only abnormal chest radiograph), gastrointestinal (25%), genitourinary tract (23%), pulmonary (19%), and neurologic (16%) systems. High-frequency hearing loss occurred in 58% (11 of 19) of patients treated with cisplatin. Musculoskeletal, gastrointestinal, and urinary tract abnormalities were most frequent in patients whose treatment included RT. CONCLUSIONS: A high frequency of late effects after treatment for pediatric GCT, particularly in patients who received RT, was demonstrated. Treatment sequelae could be anticipated from the intensity and type of therapeutic modalities. Treatment-directed screening evaluations may improve quality of life in long-term survivors of pediatric GCT through timely identification of sequelae that can be prevented or ameliorated.     

Long‐term follow‐up in hematopoieticstem‐cell transplant patients

Abstract: Hematopoietic stem‐cell transplantation (HSCT) has increasingly become an accepted treatment for many childhood diseases and disorders. Potential HSCT recipients can be children with hematological malignancies or solid tumors, as well as congenital and acquired disorders. In the past decade, the use of HSCT in the treatment of pediatric disorders has grown exponentially while advances in supportive care have improved survival rate, contributing to a rapidly growing population of transplant survivors. Although numerous similarities can be found between pediatric and adult long‐term HSCT survivors, this article provides a brief overview of the pediatric patients, emphasizing the aspects of surveillance and late effects. Understanding the long‐term complications that can occur after HSCT is important in determining the appropriate evaluations and medical treatment for the patient involved. The goal of this article is to assist caregivers in providing optimal care for long‐term survivors of HSCT. The initial section of this work comprises the three major causes of late effects in HSCT. It will then encompass a system review of the different potential complications that are seen with HSCT.     

Late effects of childhood malignancies seen in Western Australia.

Eighty-nine pediatric oncology patients, in remission and off treatment for at least 4 years, were reviewed annually in the Late Effects Clinic of Princess Margaret Hospital for Children in Perth, Western Australia. Interval from time of diagnosis to follow-up ranged from 4 to 23 years (mean 10.8 years). Acute lymphoblastic leukemia (ALL) (40%) and Wilms' tumor (27%) were the most common primary malignancies in this group. Late sequelae included musculoskeletal abnormalities (23 children), growth hormone deficiency (11), second tumors (9), learning difficulties (7), puberty and fertility problems (4), and hypothyroidism (4). These complications were most often related to radiation therapy. The need for prolonged, regular follow-up of survivors of childhood malignancy for early detection of late sequelae and subsequent intervention is stressed.